Malignant tumors are a common and frequently-occurring disease that seriously threatens human health, which are characterized by abnormal proliferation of cells or mutant cells. The proliferation, apoptosis and metastasis of tumor cells are closely related to the abnormality of a certain link in a series of signal transduction pathways inside and outside the cell. In these signaling pathways, a class of important molecule is protein kinase. The abnormality of protein kinase is closely related to the occurrence, development, prognosis and outcome of tumors, and is also the main cause of a series of other human diseases associated with inflammation or proliferative response. The development of drugs for targeting protein kinases is the main mean of treating related diseases. Many drugs have been approved for marketing. Such drugs have the characteristics of clear target, clear curative effect and high safety, and thus are increasingly recognised and supported in clinical medical practice.
Anaplastic lymphoma kinase (ALK) is an important member of the protein kinase family. Existing studies have shown that the overexpression, mutations and fusion proteins of ALK are directly related to various tumors, including but not limited to neuroblastoma, anaplastic large cell lymph tumor (ALCL), non-small cell lung cancer (NSCLC), inflammatory myofibroblastic tumor (IMT) and the like. The first-generation drug Crizotinib and the second-generation drug Ceritinib against for the ALK fusion gene have been marketed in 2011 and 2014, respectively, and the therapy thereof for patients with ALK-positive lung cancer has obtained significant progression free survival and objective response rate, which confirms the definite clinical value of this target. Despite the significant efficacy, due to the heterogeneity of tumors and the adaptation of tumor cells to environmental stress, more and more research reports indicate that drug-resistance of tumors and disease progression are still the inevitable fate of such patients. Furthermore, serious adverse reactions of these existing drugs, such as excessive incidence of adverse reactions in the digestive tract, hepatotoxicity and prolonged QT interval, also limit the application of such drugs.
For example, Luc Friboulet, Nanxin Li, Ryohei Katayama, Jeffrey A Engelman et al. found that: in about one year after the treatment with the first-generation ALK inhibitor Crizotininb, the drug-resistance occurred for most patients mainly by the mutation site of L1196M, G1269A, S1206Y and I1171T, among which L1196M is a gated site; and although the second-generation ALK inhibitor Ceritinib can solve the problem of the drug-resistance of the first-generation ALK inhibitor, the drug-resistance phenomenon of Ceritinib for G1202R, C1156Y, 1151T-ins, L1152R and F1174C mutation sites also occurred (The ALK Inhibitor Ceritinib Overcomes Crizotinib Resistance in Non-Small Cell Lung Cancer; Cancer Discov; April 2014; 4(6): 662-673.).
In view of this, it is of important social benefit and value for solving the above problems that new compounds with good ALK inhibitory activity and safety continue to be developed and further marketed.